Method for the production of diethyl isonitrosomalonate



Patented Aug. 18, 1953 IWETHOD FOR THE PRODUCTION OF DI- ETHYL ISONITROSOMALONATE- John C. Vander Weele,

Halbert C. White, Midl Edgar C. Britten, and and, Mich., assignors to The Dow Chemical Company, Midland, Mich., a corporation of Delaware No Drawing. Application September 8, 1951, Serial No. 245,772

This invention relates to an improved method for the production of diethyl isonitrosomalonate and diethyl acetamidomalonate. It relates in particular to a method in which diethyl isonitrosomalonate may be obtained in crystalline form, if desired, but in which diethyl acetamidomalonate may be obtained from malonic ester without necessity for isolation or purification of any intermediate, should this be desired.

The chemical literature i replete with disclosures of various ways in which diethyl acetamidomalonate may be made from malonic ester. These methods involve, in sequence, the nitrosation of malonic ester, reduction of the isonitroso compound, and acetylation of the resulting amine. A yield of diethyl isonitrosomalonate as high as 90 per cent is reported. Reduction of the isonitroso compound to the amine should proceed quantitatively, yet there are reports of 47 and 65 per cent yields of the amine, based on the original malonic ester. While other reports indicate that high overall yields of the diethyl acetamidomalonate have been attained at times in the laboratory, it has been applicants experience that the prior processes give overall yields of diethyl acetamidomalonate from diethyl malonate of the order of 50 per cent when carried out on a commercial scale, and this confirms some of the results reported in the literature. The difliculty is traceable principally to the quality of the isonitroso compound produced by the prior methods. The diethyl isonitrosomalonate has been reported to be an oily liquid. It

has been found, in carefully controlled operations, that the oily form of the isonitroso compound does not absorb th theoretical amount of hydrogen, when it is attempted to convert it to the amine. This is an indication that the oil has constituents other than the isonitroso compound. It has now been found that this compound, when pure, is a crystalline solid. Hence, yield calculations based on the weight of an allegedly pure but actually impure oil are unreliable.

In any event, it is desired, and it is the object of this invention, to provide a method which may be used in large scale operations to convert malonic ester to diethyl acetamidomalonate in high yields. A related object is to provide a method in which diethyl isonitrosomalonate may be obtained in crystalline form. Another object is to provide a method whereby malonic ester may be converted to diethyl acetamidomalonate .in good yield without necessity for isolating either of the intermediate products. 1

3 Claims. (01. 260-485) In accordance with the present invention, the foregoing and related objects are attained by carrying out at least the nitrosation step of the process and preferably all of the series of reactions, in an inert solvent for diethyl malonate, diethyl isonitrosomalonate, diethyl aminomalonate, and diethyl acetamidomalonate which is separable from the desired product by distillation and which is not appreciably miscible with water. Examples of suitable solvents are methylene chloride, methylene bromide, chloroform, carbontetrachloride, ethylene chloride, ethylene bromide, ethylene chlorobromide, the trichloroethanes, the tetrachloroethanes, pentachloroethane, trichloroethylene, perchloroethylene, the monochlorop-ropanes, propylene chloride, benzene, toluene, the xylenes, ethyl benzene, monochlorobenzene, monobromobenzene, orthodichlorobenzene, and the monochlorotoluenes. Of these, the bromoand chloroaliphatic hydrocarbons, aromatic hydrocarbons (includin alkyl aromatic hydrocarbons) and the chloroaromatic hydrocarbons having boiling points at atmospheric pressure between 40 and C. are preferred. Toluene is a most convenient solvent for use in the method of the present invention.

In carrying out the reaction, diethyl malonate is diluted with from one-third of its volume to about 3 times its volume of toluene, or other of the type of solvent suggested above (preferably not over about 1.6 times a much solvent as ester being used), and there is suspended in this solution enough sodium nitrite for the nitrosation reaction. It is preferred to use at least 1.25 mols of sodium nitrite per mol of ester. The sodium nitrite should contain (or the reaction should be carried out in the presence of) from 1 to 10, and preferably from 3 to 5 per cent by weight of water based on the weight of sodium nitrite. If less water is present, the reaction does not proceed satisfactorily, While, if more water is present, the disadvantages of the prior art processes are encountered, and yields are low in both cases. Glacial acetic acid is added gradually to the suspension of sodium nitrite in the toluene solution of diethyl malonate. The nitrous acid, liberated by the reaction between acetic acid and sodium nitrite in the presence of the stated limited amount of Water, reacts smoothly with the diethylmalonate, and there is precipitated the by-product sodium acetate. When the nitrosation reaction is complete, the solution of diethyl isonitrosomalonate in toluene, or other water-immiscible solvent, is treated to remove sodium acetate.

pared, and this solution can be reduced to diethyl aminomalonate by the action of ihydto e scvcr palladium-on-charcoal as thescata-lyst. After reduction, the solution of theester-ofaminoma-lonic acid is filtered away from the catalyst. Acetic anhydride is added to the solution to acetylate the v amine, and the reaction is eiiected in the presence of ice to prevent runaway temperatures. The diethyl acetamidomalonate is obtained in crystalline form, after the acetylation reaction, by concentration of itssolutionin toluene or other inert solvent and m-ixing the concentrate with water. The solvent may be recovered and reused in the process.

:In attempts to carry out'the process here concerned, under various conditions, the following observations were When all of the reagents are dry, the nitrosation reaction does not proceed satisfactorily, there is residual nitrous acid andsometimes residual sodium nitrite when thereactionshou-ld be complete, and the-resulting scl-utien of presumed diethyl isonitrosoinalonate absorbs littleihydr-ogen, often from to 50 per cent of the amount theoreticallyrequired to form the amine. When there is over 10 percent as much water as sodium nitrite, brown fumes of the oxides of nitrogen. are evolved, showing low efficie'ncy in the nitrosation and suggesting side reactions may be occurring, and a low yield of the desired isonitr'oso compound is obtained. When the required water is introduced along with the .acetic'acid by dilution of that reagent, the initial reaction rate is lower than when all the water is introduced at the start of the reaction. When the temperature of nitrosation is 30 C. or lower, there is little reaction, while at temperatures of 70 C. or higher the reaction does not produce the desired compound in yields of over 50 per cent in most cases, yet temperatures of 40 to '60 C. favor smooth, rapid reactions and good yields. The .yields fall off somewhat from the preferred high levelif the original malonic ester is dissolved in much more than-1.6 times its own volume of the water-immiscible inert solvent, and the advantage of using such a solvent is lost if its volume .is .m-uch rless than one-third that of the malonic ester.

:The following examples illustrate both labora- .tory scale and commercial scale operation of the process.

Example 1 The following materials were mixed in a oneliter flask fitted with stirrer, thermometer, dropping funnel and reflux condenser:

To this mixture, warmed to 40 0., there was added dropwise over the course of two hours 1.66 mols (100 g.) of glacial acetic acid. Periodic QQI ng .was necessary. .to keep the temperature of 4 C. When all the acetic acid had been added, stirring was continued for another four hours. There was then added 200 ml. of water to dissolve the sodium acetate and unreacted nitrous acid. "Ijhe toluene solution separated from the .aqueous layer and rewa'shed .with dilute (5 per cent) sodium chloride solution. After separatthe saline wash liquor, the toluene solution hydrogenated at 30 to 50 pounds per square ug )fpres'sure at 49 to 50 C, over 5 per pailladiuin-on-charcoal catalyst. The mix- :ture t0Qk.'lip 1. 9418 Qm'ols of hydrogen, or 97.4 per c'e t 'ftheltheoretical amount. The toluene soluwa's 'filtered away from the catalyst and was madden-breasts "with 160 ml. of acetic anhydridc. rsuiiicient ice was added to keep the tempei ature below 20 C. Most of the toluene was distilled away from the mixture, and 800 ml. of water was added to hydrolyze the excess acetic anhydride. The mixture was concentrated to 4o0:1 1 i1.. vo1ume under vacuum. Cr'ystals'separated nuring the'ccncentration step and when themixture was chilled a mass of crystals .was obtain-ed 'which weighed l idgrams after being washediw-ith ice water and dried. Further con- -centration of the filtratesyielded an additional 16 grams :of diethyl 'acetamidomalonate having a 'me'ltingpo'int of-9'7+99 EC. .The total yield was thus 74.8 per centoftheoretical, based on the initialcharge-ofimalonic:ester.

.Whenthe same charge was employed and the same initrosation conditions were used, the toluene solution of :diethyl isonitrosomalonate, aiterfi ltration toxremovemost of the sodium acetate,:could be heateduto distill part of the toluene and the remaining solution, on cooling, yielded successive crops .of crystalline die'thyl 'isonitrosomalonate. .On recrystallization, it melted at 586.-5-88.C.

Em 'pze 2 ,[nto a LOO-gallon glass-linedkettle there was s arse I Pounds piethylmalonate 160 ,S odiumnitrite 93 ma n"; 4 Toluene 200 {The mixture was stirred vigorously and was treated the :course of four hours with pounds ot-glacial acetic acid, with the reaction temperature being heldat '50-57 C. Any liberated oxidesof nitrogen were absorbed. in a waterwashed scrubbing tower. Stirring was continued an 'additioi-ia-l tour hours at the same temperature. The mixture contained considerable undissolved sodiumecetate, and "this was removed by Washing w-ith '2'5 U. S. gallons of water and then with'two successive batches of the same volume of 5 per-cent salt solution. The organic layer was pumped to ;a stainless steel autoclave where it was'mixed with -5 pounds of '5 per cent palladiumoh--charcoal. The vessel wassealed, air Wasswept out with nitrogen, and the solution washydroe ger ated at 50 100 poundsgaug'e pressure at 50 C. Hydrogenation proceeded smoothly, and alittle over 4 poundsof hydrogen had been absorbed in four-hours. The'tol-ue'nesolution was filtered away fromthe 'c'atalys t and was. mixed with 1 00 pounds-oi crushed ice and "108 pounds of acetic anhydride. The ternperatur e did not rise above 30 c. -=A-fter thorough inixing', toluenewas remo ed atsamni metrs absolute ressure. About 15. gal lons-0f water was asses" anti en-additional the- -s1 ightlyexothermic reactionfrom exceeding 7 15 gallons of distillate removed, containing much of the by-product acetic acid. The residue was cooled in a large steel tub, and diethyl acetamidomalonate crystallized out. The mixture stood overnight and the crystals were recovered in a centrifugal filter. After being washed with ice water, and dried, they weighed 167.5 pounds, representing a yield of 77 .2 per cent of theory.

The recovered toluene was washed with water to remove acetic acid, and was used with like results in the next batch.

When Example 1 was repeated using 400 grams of toluene, instead of 200 grams, the yield of the final acetamidomalonate was down to '73 per cent, and when only 50 grams of toluene was used a yield of 71 per cent was obtained. When the toluene was omitted entirely, yields of only 45 to 50 per cent were experienced.

The invention has been illustrated with toluene as the inert, water-immiscible solvent. The invention is not so-limited, however, as any solvent may be used which is inert to the reagents employed and is immiscible with water and readily separable by distillation from the desired product.

We claim:

1. A method which comprises dissolving diethyl malonate in from one-third to 3 times its volume of a water-immiscible inert solvent which is separable by distillation from the final product; suspending in said solution at least as many mols of sodium nitrate as the number of mols of diethyl malonate present, and from 1 to per cent by weight of water, based on the weight of sodium nitrate; and adding glacial acetic acid gradually to the suspension while the latter is maintained at a temperature between 30 and C. until the nitrosation of the ester is complete.

2. The method as claimed in claim 1 in which the inert solvent is toluene.

3. A method which comprises dissolving diethyl malonate in from one-third to 3 times its volume of a water-immiscible inert solvent which is separable by distillation from the final product; suspending in said solution at least as many mols of sodium nitrite as the number of mols of diethyl malonate present, and from 1 to 10 per cent by weight of water, based on the weight of sodium nitrite; adding glacial acetic acid gradually to the suspension while the latter is maintained at a temperature between 30 and 70 C. until the nitrosation of the ester is complete; separating the solution from undissolved sodium acetate; and recovering crystalline diethyl isonitrosomalonate from the solution.

JOHN C. VANDER WEELE. EDGAR C. BRITTON. HALBERT C. WHITE.

References Cited in the file of this patent UNITED STATES PATENTS Name Date Tishler et al Sept. 12, 1950 OTHER REFERENCES Number Organischen 

1. A METHOD WHICH COMPRISES DISSOLVING DIETHYL MALONATE IN FROM ONE-THIRD TO 3 TIMES ITS VOLUME OF A WATER-IMMISCIBLE INERT SOLVENT WHICH IS SEPARABLE BY DISTILLATION FROM THE FINAL PRODUCT; SUSPENDING IN SAID SOLUTION AT LEAST AS MANY MOLS OF SODIUM NITRATE AS THE NUMBER OF MOLS OF DIETHYL MALONATE PRESENT, AND FROM 1 TO 10 PER CENT BY WEIGHT OF WATER, BASED ON THE WEIGHT OF SODIUM NITRATE; AND ADDING GLACIAL ACETIC ACID GRADUALLY TO THE SUSPENSION WHILE THE LATTER IS MAINTAINED AT A TEMPERATURE BETWEEN 30* AND 70* C. UNTIL THE NITROSATION OF THE ESTER IS COMPLETE. 